Mechanisms of resistance to antibody–drug conjugates in cancers

Cancer treatment has evolved dramatically in recent years with the advent of various modalities, including molecular-targeted drugs, monoclonal antibodies, immune checkpoint inhibitors, bispecific antibodies, and chimeric antigen receptor T-cell therapy. Antibody–drug conjugates (ADCs) represent an important breakthrough in cancer treatment, and some ADCs have been approved for use in several types of cancers. Typical ADCs include trastuzumab emtansine for HER2-positive breast cancer, sacituzumab govitecan for triple-negative breast cancer (TNBC), and trastuzumab deruxtecan (T-DXd) for HER2-positive breast cancer, gastric cancer, and HER2 mutation-positive non-small cell lung cancer. Although they have shown therapeutic efficacy, almost all patients develop resistance via multiple mechanisms. In this article, we discuss the major mechanisms of resistance to ADCs, classifying them into five categories: mechanisms related to ‘target antigen,’ ‘decreased internalization,’ ‘lysosomal dysfunction,’ and ‘payload sensitivity’ and other resistance mechanisms [Figure 1]. We also discuss the strategies for overcoming ADC resistance.